Malaria remains a major threat to public health in Africa. However, renewed and expanded emphasis by the major stakeholders including African heads of state, governmental and non-governmental organizations including major philanthropic organizations and leaders in the public health community have changed the international conversation from a focus on malaria control to a focus on regional elimination and eventual eradication of malaria. Accomplishing these goals will require a multifaceted approach, making best use of existing tools and will require the development of new tools including vaccines and new drugs. Equally important will be the tailoring of the interventions and their implementation to the specific microenvironments throughout endemic Africa. In the proposed work, four sites in West Africa each with a unique epidemiological and ecological environment will be compared and contrasted with regard to intensity and prevalence of infection, vector mosquito population dynamics, including insecticide resistance, disease pathogenesis with a focus on host factors and the immune response and the emergence and spread of drug resistance. The hypothesis underlying this proposal is that a combination of parasite, human and vector factors determine the disease outcome in the individual and more broadly in the community. Both the ecological environment and the parasite modulate the disease outcome on an individual and population level, and this proposal seeks to understand the relationship between these external factors and the underlying genetic determinants in the host, parasite and vector populations. Advances both in implementation capacity and in tools for the interrogation of host, parasite and vector biology over the last five years has enabled us to undertake these studies in an unprecedented manner. Understanding these relationships is critical to both the evaluation of current intervention effectiveness and in the translation of new tools for prevention and treatment of the disease and its transmission.